1. Field of the Invention
The present invention relates generally to the fields of inflammatory responses and natural chemokine action. More particularly, it concerns the methods of making and using of novel chemokine-like genes and proteins from MCV type 1 and the closely related MCV type 2.
2. Description of Related Art
Poxviruses are notorious for their ability to evade the host's immune system by both active and passive mechanisms (Pickup, 1994). Since the eradication of smallpox, the only poxvirus that naturally infects humans is molluscum contagiosum virus (MCV). MCV causes benign proliferative lesions of the skin in normal and immunocompromised individuals. Persons with acquired immune deficiency syndrome (AIDS) sometimes get extensive MCV infections which can be disfiguring (Ray and Gateley III, 1994; Smith et al., 1994).
There are at least two types of MCV based on restriction endonuclease cleavage patterns of viral DNA (Darai et al., 1986; Porter et al., 1989; Thompson et al., 1990). Some epidemiological studies have been reported, but there is no consensus on anatomic or patient group distribution of the two MCV types. Although MCV cannot be propagated in tissue culture, the inventors and others have shown recently that MCV can be grown in human tissue implanted into immunodeficient mice (Buller et al., 1995; Fife et al., 1996).
Recently, much attention has been focused on chemokines, small proteins produced by lymphocytes and a variety of other cells. Chemokines were originally identified by their ability to attract inflammatory cells, but they have since been shown to have a variety of additional activities (for review, see Baggiolini et al., 1994). In addition to chemotaxis, some chemokines have been shown to cause decreased growth of hematopoietic stem and early subsets of myeloid progenitor cells (Broxmeyer et al., 1995; Broxmeyer et al., 1993; Broxmeyer et al., 1990; Graham et al., 1990) and some have been shown to block entry of human immunodeficiency virus into lymphocytes (Cocchie et al., 1995; Oberlin et al., 1996). Roles for chemokines in a variety of allergic and autoimmune diseases have also been postulated, although direct evidence is limited (for review see Mantovani et al., 1996).
It has been assumed that MCV, like other poxviruses, has immune evasion functions. The recent report of the nucleotide sequence of the MCV genome (Senkevich et al., 1996) has permitted identification of potential candidate viral proteins that may be involved in escape from the host immune system. One such putative viral protein is designated MC148R. This open reading frame potentially encodes a 104 amino acid protein with significant homology to .beta. chemokines such as macrophage inflammatory protein (MIP)-1.beta. (SEQ ID NO:6). The putative MC148R protein contains a five amino acid deletion at the functionally important amino terminus of the mature protein, relative to MIP-1.beta. (Senkevich et al., 1996). Only three other viruses, human herpes virus 6 (Gompels et al., 1995), human herpes virus 8 (Moore et al., 1996; Nicholas, 1997) and murine cytomegalovirus (MacDonald et al., 1997) are known to encode chemokine analogs. These herpesvirus chemokine analogs do not contain deletions, although there is only limited information about their ability to function as chemokine agonists.
There are important issues regarding this MCV viral protein that need to be resolved. It needs to be determined whether this protein may act as a chemokine agonist, if so, are there other chemokines agonists expressed by MCV. The pathogenic role of MCV viral proteins play is unknown. Further there is little information on how MCV infection escapes immune attack from the host, the presence of MCV viral protein and other proteins related to this protein may somehow effect immune system escape. The answers to these question would have many benefits in the treatment of viral infection as well as effecting immune escape in cells in which it would be desirable to suppress the host immune system.